Gamma/delta T cells are one of the least understood components of the immune system. While these cells appear to contribute uniquely to host immune competence, it has been difficult to define their function in the context of host biology or pathology. This is largely because it is unclear what the gamma/delta T cell repertoire is directed against. Previously, we have identified T10/T22 as natural ligands of gamma/delta T cells. Based on the analysis of this system, we postulate that classical and other non-classical MHC molecules, which are induced or otherwise regulated during immune responses, are biologically important gamma/delta T cell ligands. To test this, we have surveyed mice with tetramers of classical and non-classical MHC molecules. Our preliminary results show that sizable populations ofgamma/delta T cells can be identified with the class II MHC, I-Ek, and the non-classical MHCs, CD1d and Qa-1. This suggests that considerable fraction of the gamma/delta TCR repertoire is specific for MHC or MHC-like molecules. Moreover, while the peptides bound to I-E k may not be important for the specificity of recognition, glycolipids bound to CD1d and peptides bound to Qa-1 seem to dominate the specificity. We will extend these studies to include surveys with more sensitive liposomal staining reagents and to analyze the nature of ligand recognition by these specific gamma/delta T cells. Our goal is to gain a better understanding of the gamma/delta TCR repertoire, the manner in which it is regulated and the role of these specificities in the larger context of an immune response.